Excessive or prolonged exposure to peripheral infections may be permissive to cognitive and behavioral complications in the elderly. We have recently reported that peripheral stimulation of the innate immune system with lipopolysaccharide (LPS) causes an exaggerated brain inflammatory cytokine response and prolonged sickness behavior in aged Balb/c mice. While transient exposure to cytokines is beneficial in the host's response to a pathogen, excessive or prolonged exposure is associated with a myriad of neurobehavioral complications including mood, cognitive, and depressive disorders. Here, we provide novel evidence that this LPS-exacerbated inflammatory cytokine response in the brain of aged mice promotes depressive-like behaviors that are evident even after the acute effects of LPS have been resolved. Furthermore, our preliminary findings suggest that these age-related depressive-like symptoms following LPS challenge are associated with increased cytokine-mediated indoleamine 2, 3-dioxgenase (IDO) activity and altered serotonin (5-HT) metabolism in the brain. In this application, we will test the hypothesis that activation of peripheral innate immune system in the aged promotes an exaggerated inflammatory response in the brain that disrupts the normal metabolism of the neurotransmitter serotonin causing pronounced and prolonged depressive-like symptoms. To address this issue, we propose two specific aims using an aged mouse model. In the first aim we will characterize depressive-like behavior in mice challenged with LPS using two distinct behavioral tests: forced swimming and sucrose preference, and determine if neuroinflammatory pathways are associated with these age-related alterations in behavior. In the second aim we will delineate if prolonged depressive-like symptoms in aged mice following LPS challenge are a consequence of impaired tryptophan (TRP) and 5-HT metabolism in the brain. Successful completion of this project will yield a better understanding of the relationship between cytokines and depression in the aged. It is known that the elderly have a higher incidence of mood and depressive disorders concomitant with illness or infection; however, the mechanisms involved are not well understood. To address this issue we have designed behavioral and biochemical experiments using a BALB/c mouse model of aging to determine if age-associated changes in the brain are permissive to the onset of depression following activation of the peripheral innate immune system. We hypothesize that a heightened inflammatory cytokine response in the brain disrupts normal serotonin metabolism and results in long- lasting depressive symptoms. [unreadable] [unreadable] [unreadable]